tbuckley/cabot-search huggingface dataset:
A Bilayer Membrane Doped with Struvite Nanowires for Guided Bone Regeneration
Authors: Yuwei Zhu, Jianpeng Zhou, Bingyang Dai, Wei Liu, Jiangpeng Wang, Quan Li, Jun Wang, Lei Zhao, To Ngai
Journal: Advanced Healthcare Materials (2022)

Guided bone regeneration (GBR) therapy demonstrates a prominent curative effect on the management of craniomaxillofacial (CMF) bone defects. In this study, a GBR membrane consisting of a microporous layer and a struvite-nanowire-doped fibrous layer is constructed via non-solvent induced phase separation, followed by an electrospinning procedure to treat critical-sized calvarial defects. The microporous layer shows selective permeability for excluding the rapid-growing non-osteogenic tissues and potential wound stabilization. The nanowire-like struvite is synthesized as the deliverable therapeutic agent within the fibrous layer to facilitate bone regeneration. Such a membrane displays a well-developed heterogeneous architecture, satisfactory mechanical performance, and long-lasting characteristics. The in vitro biological evaluation reveals that apart from being a strong barrier, the bilayer struvite-laden membrane can actively promote cellular adhesion, proliferation, and osteogenic differentiation. Consequently, the multifunctional struvite-doped membranes are applied to treat 5 mm-sized bilateral calvarial defects in rats, resulting in overall improved healing outcomes compared with the untreated or the struvite-free membrane-treated group, which is characterized by enhanced osteogenesis and significantly increased new bone formation. The encouraging preclinical results reveal the great potential of the bilayer struvite-doped membrane as a clinical GBR device for augmenting large-area CMF bone reconstruction.
Immune-regulating camouflaged nanoplatforms: A promising strategy to improve cancer nano-immunotherapy
Authors: Biao-Qi Chen, Yi Zhao, Yang Zhang, Yu-Jing Pan, Hong-Ying Xia, Ranjith Kumar Kankala, Shi-Bin Wang, Gang Liu, Ai-Zheng Chen
Journal: Bioactive Materials (2022)

Although nano-immunotherapy has advanced dramatically in recent times, there remain two significant hurdles related to immune systems in cancer treatment, such as (namely) inevitable immune elimination of nanoplatforms and severely immunosuppressive microenvironment with low immunogenicity, hampering the performance of nanomedicines. To address these issues, several immune-regulating camouflaged nanocomposites have emerged as prevailing strategies due to their unique characteristics and specific functionalities. In this review, we emphasize the composition, performances, and mechanisms of various immune-regulating camouflaged nanoplatforms, including polymer-coated, cell membrane-camouflaged, and exosome-based nanoplatforms to evade the immune clearance of nanoplatforms or upregulate the immune function against the tumor. Further, we discuss the applications of these immune-regulating camouflaged nanoplatforms in directly boosting cancer immunotherapy and some immunogenic cell death-inducing immunotherapeutic modalities, such as chemotherapy, photothermal therapy, and reactive oxygen species-mediated immunotherapies, highlighting the current progress and recent advancements. Finally, we conclude the article with interesting perspectives, suggesting future tendencies of these innovative camouflaged constructs towards their translation pipeline.
Functional map of SARS-CoV-2 3CL protease reveals tolerant and immutable sites
Authors: Sho Iketani, Seo Jung Hong, Jenny Sheng, Farideh Bahari, Bruce Culbertson, Fereshteh Fallah Atanaki, Arjun K. Aditham, Alexander F. Kratz, Maria I. Luck, Ruxiao Tian, Stephen P. Goff, Hesam Montazeri, Yosef Sabo, David D. Ho, Alejandro Chavez
Journal: Cell Host & Microbe (2022)
The Genomic Basis of Evolutionary Novelties in a Leafhopper
Authors: Zheng Li, Yiyuan Li, Allen Z Xue, Vy Dang, V Renee Holmes, J Spencer Johnston, Jeffrey E Barrick, Nancy A Moran
Journal: Molecular Biology and Evolution (2022)

Abstract Evolutionary innovations generate phenotypic and species diversity. Elucidating the genomic processes underlying such innovations is central to understanding biodiversity. In this study, we addressed the genomic basis of evolutionary novelties in the glassy-winged sharpshooter (Homalodisca vitripennis, GWSS), an agricultural pest. Prominent evolutionary innovations in leafhoppers include brochosomes, proteinaceous structures that are excreted and used to coat the body, and obligate symbiotic associations with two bacterial types that reside within cytoplasm of distinctive cell types. Using PacBio long-read sequencing and Dovetail Omni-C technology, we generated a chromosome-level genome assembly for the GWSS and then validated the assembly using flow cytometry and karyotyping. Additional transcriptomic and proteomic data were used to identify novel genes that underlie brochosome production. We found that brochosome-associated genes include novel gene families that have diversified through tandem duplications. We also identified the locations of genes involved in interactions with bacterial symbionts. Ancestors of the GWSS acquired bacterial genes through horizontal gene transfer (HGT), and these genes appear to contribute to symbiont support. Using a phylogenomics approach, we inferred HGT sources and timing. We found that some HGT events date to the common ancestor of the hemipteran suborder Auchenorrhyncha, representing some of the oldest known examples of HGT in animals. Overall, we show that evolutionary novelties in leafhoppers are generated by the combination of acquiring novel genes, produced both de novo and through tandem duplication, acquiring new symbiotic associations that enable use of novel diets and niches, and recruiting foreign genes to support symbionts and enhance herbivory.
Signatures of Convergent Evolution and Natural Selection at the Alcohol Dehydrogenase Gene Region are Correlated with Agriculture in Ethnically Diverse Africans
Authors: Michael A McQuillan, Alessia Ranciaro, Matthew E B Hansen, Shaohua Fan, William Beggs, Gurja Belay, Dawit Woldemeskel, Sarah A Tishkoff
Journal: Molecular Biology and Evolution (2022)

Abstract The alcohol dehydrogenase (ADH) family of genes encodes enzymes that catalyze the metabolism of ethanol into acetaldehyde. Nucleotide variation in ADH genes can affect the catalytic properties of these enzymes and is associated with a variety of traits, including alcoholism and cancer. Some ADH variants, including the ADH1B*48His (rs1229984) mutation in the ADH1B gene, reduce the risk of alcoholism and are under positive selection in multiple human populations. The advent of Neolithic agriculture and associated increase in fermented foods and beverages is hypothesized to have been a selective force acting on such variants. However, this hypothesis has not been tested in populations outside of Asia. Here, we use genome-wide selection scans to show that the ADH gene region is enriched for variants showing strong signals of positive selection in multiple Afroasiatic-speaking, agriculturalist populations from Ethiopia, and that this signal is unique among sub-Saharan Africans. We also observe strong selection signals at putatively functional variants in nearby lipid metabolism genes, which may influence evolutionary dynamics at the ADH region. Finally, we show that haplotypes carrying these selected variants were introduced into Northeast Africa from a West-Eurasian source within the last ∼2,000 years and experienced positive selection following admixture. These selection signals are not evident in nearby, genetically similar populations that practice hunting/gathering or pastoralist subsistence lifestyles, supporting the hypothesis that the emergence of agriculture shapes patterns of selection at ADH genes. Together, these results enhance our understanding of how adaptations to diverse environments and diets have influenced the African genomic landscape.
Quantifying inequities in COVID-19 vaccine distribution over time by social vulnerability, race and ethnicity, and location: A population-level analysis in St. Louis and Kansas City, Missouri
Authors: Aaloke Mody, Cory Bradley, Salil Redkar, Branson Fox, Ingrid Eshun-Wilson, Matifadza G. Hlatshwayo, Anne Trolard, Khai Hoan Tram, Lindsey M. Filiatreau, Franda Thomas, Matt Haslam, George Turabelidze, Vetta Sanders-Thompson, William G. Powderly, Elvin H. Geng
Journal: PLoS Medicine (2022)

Equity in vaccination coverage is a cornerstone for a successful public health response to COVID-19. To deepen understanding of the extent to which vaccination coverage compares with initial strategies for equitable vaccination, we explore primary vaccine series and booster rollout over time and by race/ethnicity, social vulnerability, and geography.
CD39 <sup>+</sup> tissue-resident memory CD8 <sup>+</sup> T cells with a clonal overlap across compartments mediate antitumor immunity in breast cancer
Authors: Yong Joon Lee, Jee Ye Kim, Seung Hyuck Jeon, Heejin Nam, Jae Hyung Jung, Minwoo Jeon, Eui-Soon Kim, Soong June Bae, Juneyoung Ahn, Tae-Kyung Yoo, Woo Young Sun, Sung Gwe Ahn, Joon Jeong, Su-Hyung Park, Woo Chan Park, Seung Il Kim, Eui-Cheol Shin
Journal: Science Immunology (2022)

Despite being a standard treatment option in breast cancer, immune checkpoint inhibitors (ICIs) are only efficacious for a subset of patients. To gain a better understanding of the antitumor immune response in breast cancer, we examined the heterogeneity of CD8 + T cells in tumors, metastatic lymph nodes (mLNs), and peripheral blood from patients with early breast cancer ( n = 131). Among tissue-resident memory CD8 + T (T RM ) cells, including virus- and tumor-specific CD8 + T cells, CD39 expression was observed in a tumor-specific and exhausted subpopulation in both tumors and mLNs. CD39 + T RM cells from tumors and mLNs exhibited a phenotypic similarity and clonally overlapped with each other. Moreover, tumor or mLN CD39 + T RM cells clonally overlapped with CD39 − T RM and non-T RM cells in the same compartment, implying a tissue-specific differentiation process. These inter-subpopulationally overlapping CD39 + T RM clonotypes were frequently detected among effector memory CD8 + T cells in peripheral blood, suggesting a systemic clonal overlap. CD39 + T RM cell enrichment was heterogeneous among molecular subtypes of breast cancer, which is associated with the different role of antitumor immune responses in each subtype. In vitro blockade of PD-1 and/or CTLA-4 effectively restored proliferation of CD39 + T RM cells and enhanced cytokine production by CD8 + T cells from tumors or mLNs, particularly in the presence of CD39 + T RM enrichment. This suggests that CD39 + T RM cells have a capacity for functional restoration upon ICI treatment. Thus, our study indicates that CD39 + T RM cells with a clonal overlap across compartments are key players in antitumor immunity in breast cancer.
Highlights of This Issue
Journal: Clinical Cancer Research (2015)

Simultaneous blockade of MAPK and PI3K pathway signaling in tumors can preempt adaptive resistance and achieve synergistic cell killing. Clinical application of this approach, however, has proven elusive due to an increased prevalence of dose-limiting toxicity. Dreaden and colleagues address this unmet need by developing a tumor-targeting nanoscale drug formulation based layer-by-layer (LbL) self-assembly that horizontally blocks MAPK and PI3K signaling in mouse models of breast carcinoma. The authors observed further enhanced drug synergy following co-encapsulation, tumor-targeted drug delivery, and disease stabilization following systemic administration—importantly—in the absence of hepatic and renal toxicity observed with the free drug combination.Peripheral neuropathy is a common adverse effect of chemotherapy that can lead to possible cessation of therapy with no effective treatments or genetic markers to predict those at risk. Using an integrative genome-wide approach that included cell-based and patient data led to the identification of genes contributing to paclitaxel induced peripheral neuropathy in Asians and common to Europeans and Asians. Two genes, AIPL1 and BCR, were functionally validated in a stem cell-derived neuronal cell model. This approach may help prioritize target genes associated with peripheral neuropathy, leading to the development of future neuroprotective agents and personalized cancer treatments.The human papillomavirus (HPV) oncoproteins are attractive targets for cancer immunotherapy, but evidence that human T cells directed against these antigens can target HPV+ tumors is limited. Draper and colleagues identified from the TIL of a patient with metastatic anal cancer a high avidity T-cell receptor (TCR) targeting HPV-16 E6. They found that T cells genetically engineered to express this TCR were capable of recognizing HPV-16+ oropharyngeal and cervical cancer cell lines. This research provides the preclinical basis for a clinical trial of TCR genetically engineered T cells targeting HPV-16 E6 that is now active.Tumor development is a dynamic process with genetic heterogeneity observed both in space and time. To investigate the genomic landscape of pheochromocytoma, Crona and colleagues investigated 136 tumor samples from 94 patients and describe genetic heterogeneity at all levels: between patients, between different tumor lesions of the individual patient, and within tumor lesions. Of particular notice are the observed pregnant differences between paired primary and metastatic tumor lesions. Clonal classification allowed for reconstructing the life history of individual tumors identifying somatic mutations as well as specific copy number losses as early events in pheochromocytoma tumorigenesis.
Highlights of This Issue
Journal: Clinical Cancer Research (2015)

Multiple myeloma (MM) cells upregulate MHC class I molecules that serve as ligands to killer immunoglobulin-like receptors (KIR) on natural killer (NK) cells. IPH2101 is an anti-KIR, checkpoint inhibitor antibody that promotes NK cell cytotoxicity against MM. Lenalidomide's favorable immunomodulatory properties may be lost when combined with dexamethasone, thus a phase I trial of IPH2101 and lenalidomide was conducted. Results suggest the combination was safe, well tolerated, and a 24-month progression-free survival median was observed. This steroid-sparing combination is the first demonstration of “dual innate immune therapy” for MM.HER family expression heterogeneity and plasticity in response to therapeutic intervention are important drivers of primary and acquired drug resistance and pose challenges to effective cancer treatment. To address these challenges, Jacobsen and colleagues have generated Pan-HER, a mixture of six antibodies targeting EGFR, HER2, and HER3. By downmodulating all three targets simultaneously, compensatory receptor upregulation is prevented, and the receptors are rendered unavailable for ligand binding and activation. Pan-HER represents a novel strategy to deal with both primary and acquired resistance and may constitute a viable alternative in the clinic.It is well established that there is substantial genetic intratumoral heterogeneity (ITH) in clear cell renal cancer (ccRCC). Stewart and colleagues use a unique set of sunitinib-naïve and -treated ccRCC samples from patients with metastatic disease enrolled in clinical trials to evaluate the effect of targeted therapy on ITH. Following sunitinib therapy, there was increased ITH of tumor grade, renal cancer driver gene mutations, and protein expression. These results suggest that the commonly proposed mechanism of drug treatment enforcing clonal selection of a pre-existing clone should be reconsidered.Previous work in the Dietz lab at the Mayo Clinic has shown that CD14+HLA-DRlo/neg monocytes are potent suppressors of the immune system. In this study, Gustafson and colleagues provide compelling evidence for the use of CD14+ cells in tumors as a prognostic biomarker in renal cell carcinoma. The abundance of intratumoral CD14+ cells correlated with CD14+HLA-DRlo/neg monocytes in peripheral blood in RCC patients, providing a potential model for tumor-mediated systemic immunosuppression. Finally, CD14+ cells and tumor cells were found to mutually influence each other, suggesting a new, nonimmune-mediated role of monocytes in tumors.
Highlights of This Issue
Journal: Clinical Cancer Research (2015)

This study demonstrates the superiority of [68Ga]-DOTATATE PET/CT compared with all other currently used functional imaging modalities in patients with SDHB mutation-related pheochromocytomas/paragangliomas, including the currently recommended functional imaging method of choice [18F]-FDG PET/CT. These results might initiate a change in future guidelines to shift towards the use of [68Ga]-DOTA-peptides. The results of this study imply that these patients, who often suffer from metastatic disease and otherwise have limited treatment options, may benefit from peptide receptor radionuclide therapy or even treatment with so-called “cold” synthetic somatostatin analogs, which could become new important treatment options for SDHB-related pheochromocytomas and paragangliomas.The Trop-2 antigen is a new cancer therapeutic target. Starodub and colleagues studied it as a target for an antibody-drug conjugate by conjugating an anti-Trop-2 antibody with SN-38, the active metabolite of a well-known anticancer chemotherapeutic, camptothecin (irinotecan), in 25 heavily pretreated patients with diverse metastatic cancers. The safe and effective dose schedule for this agent, sacituzumab govitecan, given in repeated cycles, was determined to be 8-10 mg/kg given i.v. on days 1 and 8 of a 21-day cycle. The major and manageable side effect was neutropenia. Over 70% of patients showed either partial response or stable disease, with 6 surviving between 15 and &gt;20 months. These encouraging results have led to an expansion phase II trial in several cancer types.Radiotracer imaging techniques have shown great potential for the noninvasive detection of cell death and could enable rapid selection of the most efficacious treatment using a precision medicine approach. Witney and colleagues systematically compared a novel caspase-3-activatable PET probe, 18F-C-SNAT, to existing radiotracers that have previously been assessed in the clinic. They found that neither 18F-FDG, 99mTc-Annexin V, nor 18F-ML-10 could accurately measure treatment response in vivo at early time points post-therapy (24 h). In contrast, 18F-C-SNAT imaging detected caspase-3-mediated cell death in etoposide-treated cells and tumors, preparing the way for future clinical development of this radiotracer.The Cancer Genome Atlas identified squamous cancers among those with frequent genomic alterations in the PI3K-mTOR pathway, but resistance to small molecule inhibitors is observed in preclinical and clinical studies. Mohan and colleagues show that phosphorylation of AKT is correlated with sensitivity to PI3K-mTOR inhibitor, while MEK-ERK signaling as an important mediator of resistance, and target for combined therapy in preclinical models of human head and neck carcinomas. These findings suggest that MEK/ERK and PI3K/mTOR inhibition could be a more effective strategy to target this coactivated signal and transcriptional network and resistance in HNSCC with various alterations activating these pathways.
Highlights of This Issue
Journal: Clinical Cancer Research (2015)

The majority of alveolar rhabdomyosarcomas (aRMS) are driven by the oncogenic fusion protein PAX3-FOXO1. Novel therapies are needed to target PAX3-FOXO1 or pathways supporting its tumorigenic properties. To this end, Kephart and colleagues conducted a screen for genes that collaborate with PAX3-FOXO1, and identified the secreted Wnt inhibitor SFRP3. Genetic suppression of SFRP3 in aRMS cell lines decreased proliferation and increased apoptosis and differentiation. In a murine xenograft model, suppression of SFRP3 inhibited aRMS tumor growth and sensitized tumors to vincristine, part of the chemotherapeutic backbone of RMS therapy, suggesting that targeting SFRP3 may be a promising therapeutic strategy.Hong and colleagues conducted a phase I clinical trial of lenvatinib—a multikinase inhibitor of VEGFR 1–3, FGFR 1–3, PDGFRα, RET and KIT—in patients with solid tumors. The maximum tolerated dose was 10 mg twice daily. Drug-related toxicities included hypertension (43%), fatigue (42%), proteinuria (39%), and nausea (25%). Twelve patients (15.6%) achieved partial response (PR, n = 9) or unconfirmed PR (n = 3); 19 (24.7%) achieved stable disease ≥23 weeks. The toxicity profile and antitumor activity of lenvatinib are encouraging.Little is known about miRNAs in the development and treatment of T-cell lymphoblastic lymphoma (T-LBL). Using microRNA microarrays, Qian and colleagues reported, for the first time, that the downregulation of miR-374b was frequently detected in primary T-LBL tissues, which was significantly associated with worse overall survival and increased risk of recurrence. Moreover, in vitro and in vivo studies showed that miR-374b suppressed cell tumorigenicity and promoted cellular apoptosis by inhibiting AKT signal pathway though directly repressing Wnt-16 and AKT1. Targeting miR-374b pathway may represent novel prognostic biomarkers and new therapeutic strategies to improve the therapy and survival of patients with T-LBL.Cancer-associated fibroblasts (CAFs) have been associated to recurrence and survival in colon cancer. After proteomic characterization, the authors identified LOXL2 as an upregulated protein in purified colon CAFs. High expression of LOXL2 showed a clear association, either disease-free or overall survival in colon cancer patients. In addition, it displayed a significant prognostic value in the stratification of high-risk stage II and III patients. Thus, LOXL2 shows promise as a relevant tool in clinical practice for risk classification, which could lead to a more aggressive therapy and better outcomes for stage II patients.